Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms

Kennaway, David J.; Varcoe, Tamara J.; Voultsios, Athena; Salkeld, Mark D.; Rattanatray, Leewen; Boden, M. J.

doi:10.1007/s11010-014-2219-8

Cited by 13 publications

(13 citation statements)

References 36 publications

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“…This latter finding has been confirmed in a number of studies ( Badura et al, 2007 ; Walton et al, 2009 ; Meng et al, 2010 ; Kennaway et al, 2015 ) and applied in others, to examine the impact of CK1δ inhibitors on drug seeking behavior ( Bryant et al, 2009 ; Perreau-Lenz et al, 2012 ). Although PF670462 is known to be subject to rapid hepatic metabolism and has a quoted T1/2 of less than 30 min ( Wager et al, 2014 ), it is evident from the cited findings that peripheral blood levels are sufficient to achieve inhibition of the central CLOCK, and are therefore sufficient to block the target in peripheral tissues, as further indicated by control of hepatic CLOCK genes ( Kennaway et al, 2015 ). Fibrogenic gene induction was reduced (IL-6, TIMP-1) or prevented (COL-1A, COL-3) by PF670462 treatment and BAL levels of immunoreactive IL-6 ( Figure 6B ).…”

Section: Resultsmentioning

confidence: 54%

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

et al. 2018

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Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a ‘therapeutic’ regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1 δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.

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Section: Resultsmentioning

confidence: 54%

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

et al. 2018

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“…Higher-dose PF administration was reported to cause a loss in clock gene function in mice 43 . In addition, 100 mg/kg acute PF administration was reported to increase the mortality rate in these animals 44 . However, the intraperitoneal injection of 50 mg/kg PF, albeit only once, can successfully suppress allergic reactions in mice, and this was found to be under the regulation of clock genes, preventing effects on the SCN such as melatonin secretion and dark and light perception 44,45 .…”

Section: Discussionmentioning

confidence: 96%

“…In addition, 100 mg/kg acute PF administration was reported to increase the mortality rate in these animals 44 . However, the intraperitoneal injection of 50 mg/kg PF, albeit only once, can successfully suppress allergic reactions in mice, and this was found to be under the regulation of clock genes, preventing effects on the SCN such as melatonin secretion and dark and light perception 44,45 . Local PF administration via inhalation was also reported to be effective without the development of any adverse effects 46 .…”

Section: Discussionmentioning

confidence: 96%

Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia

Ihara

Nakamura

Mitsui

et al. 2019

Sci Rep

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Intermittent stress disrupts the circadian rhythm in clock genes such as Per2 only in peripheral organs without any effect on the central circadian clock in the suprachiasmatic nucleus. Here, the effect of restraint stress (RS) on circadian bladder function was investigated based on urination behavior and gene expression rhythms. Furthermore, PF670462 (PF), a Per2 phosphorylation enzyme inhibitor, was administered to investigate the effects on circadian bladder re-alignment after RS. Two-hour RS during the light (sleep) phase was applied to mice (RS mice) for 5 days. The following parameters were then examined: urination behaviors; clock gene expression rhythms and urinary sensory-related molecules such as piezo type mechanosensitive ion channel component 1 ( Piezo1 ), transient receptor potential cation channel subfamily V member 4 ( TRPV4 ), and Connexin26 ( Cx26 ) in the bladder mucosa; Per2 expression in the excised bladder of Per2 luciferase knock-in mice (Per2::luc); in vivo Per2 expression rhythms in the bladder of Per2::luc mice. Control mice did not show altered urination behavior in the light phase, whereas RS mice exhibited a higher voiding frequency and lower bladder capacity. In the bladder mucosa, RS mice also showed abrogated or misaligned Piezo1 , TRPV4 , Connexin26 , and clock gene expression. The rhythmic expression of Per2 was also altered in RS mice both in excised- and in vivo bladder, compared with control mice. After PF administration, voiding frequency was reduced and bladder capacity was increased during the light phase in RS mice; the in vivo Per2 expression rhythm was also fully restored. Therefore, RS can alter circadian gene expression in the bladder during the light phase and might cause nocturia via changes in circadian bladder function due the dysregulation of clock genes. Amending the circadian rhythm therapeutically could be applied for nocturia.

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“…The casein kinase 1 family phosphorylate over 140 additional targets associated with membrane transport processes, trafficking and microtubule associated dynamics, cell cycle progression and apoptosis (Yang Y. et al, 2017;Xu et al, 2019). Mutations in CSNK1D have been linked to familial advanced sleep phase syndrome and acute inhibition or genetic disruption results in alterations in circadian rhythms which correlates with the observation that core clock proteins are substrates for the enzyme (Xu et al, 2005;Etchegaray et al, 2009;Isojima et al, 2009;Meng et al, 2010;Brennan et al, 2013;Kennaway et al, 2015). Furthermore, it is possible that dysregulation of circadian rhythms in AD is aligned with alterations in CSNK1D function.…”

Section: Rockmentioning

confidence: 98%

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

Benn¹,

Dawson

2020

Front. Aging Neurosci.

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Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity.

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Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms

Cited by 13 publications

References 36 publications

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia

Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease

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